Opposite roles of metastasin (S100A4) in two potentially tumoricidal mechanisms involving human lymphocyte protein Tag7 and Hsp70

Abstract

We compare the physical and functional interactions between three widespread multifunctional proteins [metastasin (Mts1/ S100A4), innate immunity-related Tag7/PGRP-S, and Hsp70] in two experimental models relevant to host-tumor relationships on humoral and cellular levels.

A new role for PGRP-S (Tag7) in immune defense: lymphocyte migration is induced by a chemoattractant complex of Tag7 with Mts1

“…Our data have deepened the insight into the functional activity of Tag7 in the immune defense, showing that it forms stable complexes with Hsp70 and the Ca 2C binding protein Mts1, 9,18 with the functions of these complexes being completely different from those of their components. Indeed, the Tag7-Hsp70 complex can kill tumor cells, thereby retarding tumor growth, while Tag7 alone has no cytotoxic activity.…”

“…5,7 We have shown that Tag7 is expressed on the surface of CD4 C CD25 C lymphocytes, the highly specialized cells of the acquired immunity that participate in the killing of HLA-negative tumor cells by recognizing Hsp70 on their surface. 10,18 The latter protein is practically absent on the surface of normal cells but is exposed on tumor cells, thereby serving as an "alarm signal" for effector lymphocytes, and it is Tag7 that recognizes Hsp70 and makes a specific contact with it.…”

“…9, 17 Moreover, we have found 2 additional proteins that can interact with Tag7: the Ca 2C -binding protein S100A4 (Mts1), encoded by the gene that is highly expressed in metastatic tumors and cells of the immune system, and the cochaperone HspBP1, which inhibits the ATPase activity of Hsp70. [18][19][20][21] Their interaction with Tag7 results in the suppression of cytotoxicity of the Tag-Hsp70 complex.…”

The Heat Shock-binding Protein (HspBP1) Protects Cells against the Cytotoxic Action of the Tag7-Hsp70 Complex

“…According to our recent data (29), the Ca 2ϩ -binding protein Mts1 can also bind with Hsp70 and Tag7, this interaction resulting in Tag7 dissociation from the complex and, consequently, in complete loss of cytotoxic activity.…”

Unexpected deeds of familiar proteins: Interplay of Hsp70, PGRP S / Tag7, and S100A4 / Mts1 in host vs. cancer combat

“…A vivid example is the tumoricidal complex of two non-cytotoxic proteins, 11,13 i.e., a true binary weapon: one component is the classical chaperone Hsp70, the other is an innate immunity-related protein Tag7 (PGRP-S).…”